The Sir2 (silent information regulator 2) proteins are an evolutionally-conserved family of class III histone deacetylases (HDACs) (Bordone, et al., 2005; North et al., 2004; Baur, et al., 2006). Unlike class I and II HDACs, the catalytic activity of the Sir2 family requires the cofactor NAD, a key product of cellular metabolism. In yeast, Sir2 acts as a transcriptional repressor by deacetylating histones and its homologues have also been found to promote longevity in yeast, flies, and worms (Kaeberlein, 1999; Rogina and Helfand, 2004; Tissenbaum, 2001) indicating that it is an anti-aging gene of broad significance. In mammals, there are seven members of the Sir2 family, termed SIRTuins (SIRTs), of which SIRT1 is the closest homolog of yeast Sir2. In early studies, it was found that the tumor suppressor p53 can be dynamically regulated by acetylation and deacetylation (Gu, et al., 1997; Luo, et al., 2000; it was subsequently found that SIRT1 promotes cell survival by inhibiting apoptosis and deacetylation of p53 (Luo, et al., 2001; Langley, et al., 2001; Vaziri, et al., 2001). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in SIRT1-deficient mice (Cheng, et al., 2003).
Nevertheless, SIRT1-mediated regulation is also implicated in p53-independent pathways (Motta, et al., 2004; Brunet, et al., 2004; Kitamura, et al., 2005; Cheng et al, 2003, Chen, et al, 2005; Yeung, et al., 2004; Greene & Chen, 2004; Rodgers, et al., 2005; Cohen, et al., 2004). For example, FOXO family proteins, RelA/p65 subunit of NF-κB and Ku70 are substrates of SIRT1 and deacetylation of these factors is involved in the stress response under different cellular contexts.
Moreover, recent studies indicate that SIRT1 directly interacts with PPAR-γ and PGC-1α and modulates metabolic responses (Bordone, et al., 2005; North, et al., 2004; Baur, et al., 2006; Rodgers, et al., 2005). SIRT1 is expressed in white adipose tissue (WAT) and its levels rise in calorie restricted animals (Cohen, 2004). Moreover, SIRT1 has been shown to inhibit adipogenesis in white adipose tissue and promote fat disposal in fully differentiated white adipocytes (Picard, 2004). SIRT1 binds to the negative cofactors NCoR and SMART, and may thus inhibit the activity of the proadipogenic nuclear receptor, PPAR-γ. These studies validate the importance of the deacetylase activity of SIRT1, but it remains unclear how SIRT1-mediated deacetylation is controlled in vivo.
Further, induction of SIRT1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease (Tang, et al., 2007).